1. Field of Invention
This invention relates to tris(isonitrile) copper(I) adducts, their preparation, kits containing them, and methods of using them to prepare technetium complexes.
2. General Background and Prior Art
Isonitrile complexes of various radionuclides and their use as imaging agents are known in the art as described, for example by Jones et al. in U.S. Pat. No. 4,452,774, issued June 5, 1984. The complexes described by Jones, et al are of the general formula: EQU [A((CN).sub.x R).sub.y B.sub.z B'.sub.z' ].sup.n
in which A is a radionuclide selected from radioactive isotopes of Tc, Ru, Co, Pt, Fe, Os, Ir, W, Re, Cr, Mo, Mn, Ni, Rh, Pd, Nb, and Ta, for example, Tc99m, Tc99, .sup.97 Ru, .sup.51 Cr, .sup.57 Co, .sup.188 Re and .sup.191 Os; (CN).sub.x R is a monodentate or polydentate isonitrile ligand bonded to the radionuclide through the carbon atom of the CN group; R is an organic radical; B and B' are independently selected from other ligands well known to those skilled in the art that result in isonitrile complexes, including solvents such as water, chloro and bromo groups, and ligands comprising one or more neutral donor atoms capable of forming bonds with said radionuclide; x and y are each independently integers from 1 to 8; z and z' are each independently 0 or an integer from 1 to 7; with the proviso that (xy)+z+z' is less than or equal to 8; and n indicates the charge of the complex and can be 0 (neutral), or a positive or negative integer the value of which depends upon the valence state of A, and the charges on R, B and B'. Any desired counterion can be present as required by the charge on the complex with the proviso that such counterion must be pharmaceutically acceptable if the complex is to be used in vivo.
In the above formula, R is an organic radical that can be aliphatic or aromatic and may be substituted with a variety of groups which may or may not be charged. When the organic radical R carries a charged substituent group, the charge on the resultant complex is the summation of the charges of the ligands (R, B and B') and the charge of the radionuclide. Among the aromatic R groups which may be present are phenyl, tolyl, xylyl, naphthyl, diphenyl and substituted aromatic groups containing such substituents as halo, e.g., chloro, bromo, iodo or fluoro; hydroxy, nitro, alkyl, alkoxy, etc.; among the aliphatic R groups which may be present are alkyl, preferably containing 1 to 20 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-hexyl, 2-ethylhexyl, dodecyl, stearyl, etc. Substituent groups may also be present in the aliphatic groups, including among others the same substituent groups as those listed above for aromatic groups.
The complexes described by Jones et al. are described as being useful for visualizing cardiac tissue, detecting the presence of thrombi in the lung and associated areas of blood perfusion deficits, studying lung function, studying renal excretion, and imaging bone marrow and the hepatobiliary system.
In practice, the technetium complex of the simple hydrocarbon isonitriles such as t-butylisonitrile preferred by Jones et al. have demonstrated somewhat high concentration in the lung and liver in humans. [Holman, et al., J. Nucl. Med., 25, 1380(1984)].
Other isonitrile complexes of radionuclides are described by Jones et al. in European Patent Appln. No. 213,945 published Mar. 11, 1987. The isonitrile ligands described therein have the formula: EQU (CNX)R,
where X is a lower alkyl group having 1 to 4 carbon atoms, R is selected from the group consisting of COOR.sub.1 and CONR.sup.2 R.sup.3 ; where R.sup.1 can be H, a pharmaceutically acceptable cation, or a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms, and R.sup.2 and R.sup.3 can be the same or different, results in a complex having the general advantages of the isonitrile radionuclide complexes of U.S. Pat. No. 4,452,774, but having generally superior properties with respect to liver clearance or lung clearance. Consequently, these complexes can allow earlier imaging, and/or better imaging of bodily tissues and organs than their corresponding parent compounds. Described are coordination complexes of Tc, Ru, Co, Pt or Re with the above isonitrile ligands.
Additional isonitrile complexes of radionuclides are described in coassigned U.S. Pat. application Ser. No. 056,003, filed June 1, 1987 (NN-0181-B), in the names of Bergstein and Subramanyan. The isonitrile ligands described therein are ether-substituted isonitriles of the formula: ##STR1## wherein A is a straight or branched chain alkyl group; and
R and R' each independently is a straight or branched chain alkyl group or taken together are a straight or branched chain alkylene group, provided that: PA0 (1) reacting in a suitable solvent about one equivalent weight of: PA0 (2) removing the solvent to provide a solid copper tris product.
(1) the total number of carbon atoms in A plus R in formula (I) is 4 to 6, provided further that when the total number of carbon atoms is 6, then the carbon atom alpha to the isonitrile group is a quaternary carbon, and PA1 (2) the total number of carbon atoms in A plus R plus R' in formula (Ia) is 4 to 9. PA1 (a) a tetrakis(acetonitrile)copper(I) BF.sub.4, PF.sub.6, or ClO.sub.4, or PA1 (b) cuprous iodide, bromide or chloride, with about three equivalent weights respectively of:
The further evaluation of isonitrile Tc99m complexes of U.S. Pat. No. 4,452,774 is described by E. Deutsch et al., J. Nucl. Med., 27, 409 (1986); M. N. Khalil et al., Nucl. Med. Cummun., 6, 615 (1985); A. G. Jones et al., J. Nucl. Med., 25, 1350 (1984); A. G. Jones et al., Int. J. Nucl. Med. Biol., 11, 225 (1984); and A. Davison et al., Inorg. Chem., 22, 2798 (1983).
One difficulty in preparing isonitrile complexes of radionuclides is that many isonitriles are extremely volatile; thus, the manufacturing of lyophilized kits for commercial purposes is not possible. Published European Patent Appln. No. 211,424, published Feb. 25, 1987, addresses this problem by preparing soluble isonitrile complexes of metals such as Cu, Mo, Pd, Co, Ni, Cr, Ag and Rh and then reacting them with the desired radionuclide. The pair of metals chosen is such that the non-radioactive metal is readily displaceable from its isonitrile complex in an appropriate media by the desired radionuclide, thus giving the desired radiopharmaceutical. The copper complexes described are (bis-isonitrile)phenanthroline and tetrakis-isonitrile complexes. A further difficulty occurs when such non-radioactive metal (e.g. Cu) isonitrile adducts are reacted with a desired radionuclide (e.g. Tc99m) to prepare a radiopharmaceutical. Many such adducts react with Tc99m at elevated temperatures to produce a radiopharmaceutical rapidly. The reaction at room temperature is slow and may take several hours to produce a high yield of the desired radiopharmaceutical.